The present invention is related to the use of a bisphosphonate for the treatment of Osteogenesis imperfecta, a hereditary disease that affects the bones and which had no effective formulations and treatment until today. More particularly, the invention is related to the use of a bisphosphonate for the manufacture of a medicament for the treatment of Osteogenesis imperfecta and a kit for the treatment of Osteogenesis imperfecta.
This invention also comprises the development of simple formulations and/or products with a combined presentation in multi-packing with the purpose of providing a pharmaceutical specialty based on the procedure of the present invention.
Osteogenesis Imperfecta also known as brittle bone disease is a rare genetic disorder that affects approximately 2.000 children in Argentina and 20.000 children in the United States. It is because of its low incidence in the population that the research and development for the formulation of products and treatments are classified as “orphans”. Due to the same reasons, published data are based on the experiences carried out, analyzed and studied in isolated cases, or very small groups of patients.
The “orphanage” in research for the development of effective formulations for the treatment of this disease, is more noticeable in the pharmaceutical industrial field, owing to the fact that it is difficult to recoup the funds which are needed for the industrial research and development of any method aimed at such a small number of potential users. Consequently, the development of a new formulation and the invention of a new procedure require a solid industrial protection that makes possible the investment needed to obtain a product that meets the standards of the present sanitary regulations.
Osteogenesis Imperfecta (OI) is a genetic disorder characterized by causing several bone fractures and deformities. It affects children since born hindering their normal growth and the development of their skeletons.
The children affected by Osteogenesis Imperfecta suffer multiple fractures. Some children may even be born with fractures produced during birth labour. Fractures may be caused by minimum pressure and therefore affect growth and survival.
The subsequent bone deformations may be the cause of a high extra-osseous morbidity and mortality rate, since they affect the normal functioning of vital organs such as the respiratory system and only those patients with the most benign form of the disease, have a better prospect to reach maturity. Therefore, bone development control determines these patients' prognosis. The main manifestation of this genetic defect is the synthesis of a very low quality collagen. In the bone, collagen is the main organic component of the tissular matrix, forming a fibrous meshwork that serves as deposit and orientation of the mineral crystals. This defective bone material fosters the development of deformities and fractures.
There also exist at least two other important factors, which affect bone fragility:
I) The restoring mechanism (a humoral cellular system which tends to renovate low-effective mineral tissue) increases bone turnover. In doing so, they worsen the calcium metabolic state, since the result of its action is Osteopenia (mineral tissue of low calcium density), fostering bone deformation.II) The scarce muscular development hinders the main physiological stimulus for the architectural development of bones, fostering the formation of bone structures which are unsuitable to bear the daily mechanical challenges. That is to say, that bone disorder caused by Osteogenesis Imperfecta is qualitative as well as quantitative, where both the mineralization and conformation of the bone are insufficient to withstand deformations and fractures.
The disease does not currently count with an effective treatment. It is difficult to modify the genetic basis of the disorder despite the fact that gene transfer—a possibility under development—has already been patented (Bonadio J., U.S. Pat. No. 5,763,416; Berg R. A., U.S. Pat. No. 5,667,839).
A different form to attenuate Osteopenia is the use of the so-called bone formation stimulators, such as fluor salts or human Interleukin 4 or its analogs.
These procedures attain a positive balance of calcium, but are not used to correct defects of bone structure and material quality. Alternatively, it has been attempted to attenuate Osteopenia (the quantitative defect of mineral density) using bisphosphonates by following the procedures applied to other diseases which cause Osteopenia, such as Osteoporosis.
In this regard, it should be taken into account that bisphosphonates are substances that inhibit the bone calcium metabolism, producing less negative and sometimes even positive results, increasing mineral density. Examples of known bisphosphonates are pamidronate, alendronate, olpadronate, risedronate, neridronate, ibandronate, zolendronate, IG-9402, etc.
Thus, the administration of bisphosphonates in children with Osteogenesis Imperfecta was started in very short cyclical schedules (for example, of only 2-3 months followed by a same period without treatment or of 15 days of treatment every 3 months) and in fixed schedules (of the same length for all patients).
Since the bones treated with these “fixed cyclical procedures” are under growth, treatment resulted in mineralization bands alternated with bands of Osteopenia, mainly in the areas of higher bone growth. The resulting mineralized tissue is of dubious mechanical efficiency (Devogelaer J. P. et al, Skeletal Radiol. 1987, 16: 360; Devogelaer J. P. et al., Medicina [Bue-nos Aires] 1997, 57 [S1]:101).
Later, the bisphosphonates were used in a different way, at small oral doses, but daily and continuously (a procedure named “continuous”). In this way, both bone resorption inhibition and an increase in total mineral density were achieved (Landsmeer-Beker EA et al., Eur. J. Pediatr. 1997, 156:792). It is not possible to assess if bone resistance to fracture improves with this procedure.